Design of a randomized controlled trial of physical training and cancer (Phys-Can) – the impact of exercise intensity on cancer related fatigue, quality of life and disease outcome

Berntsen et al. BMC Cancer (2017) 17:218
DOI 10.1186/s12885-017-3197-5

STUDY PROTOCOL

Open Access

Design of a randomized controlled trial of
physical training and cancer (Phys-Can) –
the impact of exercise intensity on cancer
related fatigue, quality of life and disease
outcome
Sveinung Berntsen1,2, Neil K Aaronson3, Laurien Buffart4, Sussanne Börjeson5, Ingrid Demmelmaier1,
Maria Hellbom6, Pernille Hojman7, Helena Igelström1, Birgitta Johansson1,8, Ronnie Pingel1, Truls Raastad9,
Galina Velikova10, Pernilla Åsenlöf11 and Karin Nordin1,2*

Abstract
Background: Cancer-related fatigue is a common problem in persons with cancer, influencing health-related
quality of life and causing a considerable challenge to society. Current evidence supports the beneficial effects of
physical exercise in reducing fatigue, but the results across studies are not consistent, especially in terms of exercise
intensity. It is also unclear whether use of behaviour change techniques can further increase exercise adherence
and maintain physical activity behaviour. This study will investigate whether exercise intensity affects fatigue and
health related quality of life in persons undergoing adjuvant cancer treatment. In addition, to examine effects of
exercise intensity on mood disturbance, adherence to oncological treatment, adverse effects from treatment,
activities of daily living after treatment completion and return to work, and behaviour change techniques effect on
exercise adherence. We will also investigate whether exercise intensity influences inflammatory markers and
cytokines, and whether gene expressions following training serve as mediators for the effects of exercise on fatigue
and health related quality of life.
Methods/design: Six hundred newly diagnosed persons with breast, colorectal or prostate cancer undergoing
adjuvant therapy will be randomized in a 2 × 2 factorial design to following conditions; A) individually tailored
low-to-moderate intensity exercise with or without behaviour change techniques or B) individually tailored high

intensity exercise with or without behaviour change techniques. The training consists of both resistance and
endurance exercise sessions under the guidance of trained coaches. The primary outcomes, fatigue and health
related quality of life, are measured by self-reports. Secondary outcomes include fitness, mood disturbance,
adherence to the cancer treatment, adverse effects, return to activities of daily living after completed treatment,
return to work as well as inflammatory markers, cytokines and gene expression.
(Continued on next page)

* Correspondence:
1
Dept. of Public Health and Caring Sciences, Lifestyle and rehabilitation in
long term illness, Uppsala University, Box 564, 75122 Uppsala, Sweden
2
Dept. of Public Health, Sport and Nutrition, University of Agder, Gimlemoen
25, 4604 Kristiansand, Norway
Full list of author information is available at the end of the article
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License ( which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
( applies to the data made available in this article, unless otherwise stated.


Berntsen et al. BMC Cancer (2017) 17:218

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(Continued from previous page)

Discussion: The study will contribute to our understanding of the value of exercise and exercise intensity in
reducing fatigue and improving health related quality of life and, potentially, clinical outcomes. The value of

behaviour change techniques in terms of adherence to and maintenance of physical exercise behaviour in
persons with cancer will be evaluated.
Trial registration: NCT02473003, October, 2014.
Keywords: Cancer, Physical exercise, Behaviour change techniques, Fatigue, Biological mechanism, Quality of life,
Randomized controlled trial

Background
Cancer-related fatigue (CRF) is a multidimensional concept including physical, social, emotional, psychological
and biological components experienced by persons treated
for cancer. The biological mechanisms underlying CRF
are not well understood [1]. CRF is reported in up to 90%
of persons with cancer during adjuvant treatment with radiation therapy, chemotherapy and/or endocrine therapies
[2, 3]. Clinically relevant levels of CRF have further been
reported in approximately one-third of cancer survivors
up to 6 years post-treatment [3, 4]. CRF has serious impact on the person’s health-related quality of life (HRQoL)
[5, 6] and causes a considerable challenge to society in
humans and economic terms [7]. Analysis shows that
cancer-related mortality costs €75 billion in Europe in
2008 due to loss of productive life [8].
Systematic reviews emphasize the potential physical and
psychosocial benefits from rehabilitation programs including physical exercise [9, 10]. Previous studies have suggested that exercise interventions in persons with cancer
may be cost-effective [11–13]. At the same time, there are
significant challenges associated with a change of lifestyle
during and following cancer treatment [14, 15]. Studies that
have evaluated the effectiveness of exercise interventions
on CRF are not consistent with respect to exercise volume
or intensity to be recommended [16, 17], highlighting the
need for more research. Despite the growing body of evidence that exercise is beneficial to persons both during and
after oncological treatment, persons still avoid exercise following the cancer diagnosis and reduce their physical activity levels [18, 19]. More research is needed regarding how
to enable individuals to become and stay physically active

[20] and which techniques [21] to use in order to facilitate
this behavioural change [22].
The results of a meta-analysis indicate that physical
exercise has a significant, clinically relevant positive effect on CRF [9, 16, 17, 23]. However, the results of randomized controlled trials are not consistent, and it is
unclear which exercise intensity level is most appropriate and most efficacious for the management of CRF.
From a methodological perspective, not all studies have
had CRF as their primary outcome, and some studies

were underpowered to detect a clinically relevant effect
of exercise [9, 16, 17, 23].
From a bio-psychosocial perspective, exercise may
comprise many different behaviours influenced by physical, psychological and contextual determinants of which
some are amenable to change and others are not. Previous research among cancer populations has identified
modifiable psychological determinants of physical exercise; the most salient being readiness to change, selfefficacy for exercise and perceived behavioural control
[24, 25]. BCTs can be used to facilitate and encourage
exercise behaviour change. This includes exploring
motivational issues (e.g., pros and cons of exercise,
readiness to change and self-efficacy for physical exercise) and using self-regulatory strategies (e.g. individual
goal-setting, self-monitoring and analysing one’s own physical exercise behaviours, and developing plans for maintenance of exercise behaviour including generalization to
various settings) [21, 26].
Endurance exercise has been shown to increase the
level of anti-inflammatory cytokines, leading to a systematic lowering of pro-inflammatory cytokine response
as part of the training adaptation and indicating a general anti-inflammatory effect of exercise [27]. There is
some evidence that this anti-inflammatory response also
depends on exercise intensity [27]. However, limited
knowledge exists in persons with cancer [28]. In addition
to anti-inflammatory responses, muscular expression of
apoptotic and metabolic markers may also be relevant to
the interplay between physical exercise and fatigue [29,
30]. While the causes of CRF among cancer survivors are

not yet fully understood, decreased fitness, as well as immune and cytokine dysregulation have been suggested to
play a role [9, 27]. Accumulating evidence also suggests
that several pathways, including chronic inflammation,
autonomic imbalance, HPA-axis dysfunction, and/or mitochondrial damage, could contribute to the disruption of
normal neuronal function and result in CRF [28].
To summarize, there is evidence supporting the beneficial effects of exercise during adjuvant treatment in
cancer persons, but the findings with regard to fatigue
are inconsistent. Also, the mechanisms through which


Berntsen et al. BMC Cancer (2017) 17:218

exercise reduces or prevents CRF are still not fully
understood. There is still a need for large-scale and welldesigned studies including persons at high risk of developing CRF during treatment [31]. In addition, more
research is needed to determine the optimal level, intensity, and type of exercise, as well as how tailored
BCTs and structured exercise regimes may contribute
to increased exercise adherence and maintenance of
physical activity behaviour throughout the cancer survivorship period [10]. Recently Barsewick et al. [1]
highlighted the need to conduct longitudinal research
on the interrelated bio-behavioural mechanisms underlying CRF, and to test mechanistic hypotheses within
the context of CRF intervention research. Few studies
have investigated the effects of physical exercise on
genetic biomarkers and systemic inflammatory markers
in cancer persons with and without CRF [31]. The
present study aims to address many of these issues.
The main aim of this randomized controlled trial,
Phys-Can, is to determine the effects of low-to-moderate
and high intensity physical exercise with or without
BCTs on CRF and HRQoL in persons with cancer, both
during treatment and in the long-term, post-treatment

survivorship period. Additionally, the trial will investigate the role of inflammation, cytokines and gene
expression in the development and maintenance of CRF,
as well as the cost-effectiveness of physical exercise programs during cancer treatment.
More specific, our objectives are to:
1. Investigate the effects of low-to-moderate intensity
exercise compared to high intensity exercise on
person-reported outcomes (CRF as primary
endpoint), chemotherapy/radiation completion rates,
medical (oncology) adverse effects, physical activity
and daily function, during adjuvant/curative
treatment and at long-term-follow up. In addition,
intervention effects on treatment tolerability and
time to recurrence of cancer will be investigated
2. Investigate if supplemental BCTs increase adherence
to and the efficacy of a physical exercise intervention
during and after adjuvant therapy.
3. Explore the regulation of systematic inflammatory
markers and muscular expression of cytokines in
response to physical training and following training
to investigate whether these serve as mediators for
the effects on physical exercise on CRF and HRQoL.
4. Evaluate the cost-effectiveness of physical exercise
interventions for CRF from a societal perspective.

Methods
The Phys-Can project is a randomized controlled trial
with a preceding descriptive observational study to be
used for comparisons.

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The purpose of the observational study is to monitor
how disease and treatment are associated with the person’s cardiorespiratory fitness, mental well-being, quality
of life and patterns of physical activity over time. The
same inclusion/exclusion criteria as in the Phys-Can
intervention study were used. Persons with breast, colorectal and prostate cancer about to begin their neoadjuvant and/or adjuvant therapy in Uppsala, Linköping and
Malmö/Lund were asked to participate. Inclusion started
15th of September 2014 and was terminated 28th of
February 2015. A total of 95 persons were included.
They followed the same intervals in terms of physical
testing and self-report questionnaires as the persons in
the Phys-Can intervention study, but were not participating in any exercise intervention. In addition to physical tests and person-reported outcomes, data from
medical records in adjunction to adjuvant treatment and
register data were collected to be used for health economic analyses.
Directly after completion of enrolment of persons in the
observational study (15th of March 2015), the inclusion to
the randomized controlled trial was started. Persons recently diagnosed with breast cancer, colorectal cancer or
prostate cancer, scheduled for neoadjuvant chemotherapy
(breast cancer) or endocrine therapy (prostate cancer),
and/or adjuvant chemotherapy (breast- and colorectal
cancer), adjuvant radiotherapy (breast cancer) and/or adjuvant endocrine therapy (breast- and prostate cancer)
or radiotherapy with curative intent without additional endocrine therapy (prostate cancer) are invited
to participate. Consecutive persons are recruited from
Uppsala, Lund/Malmö and Linköping University hospitals. Persons who are not able to perform basic activities of daily living, who show cognitive disorders
or severe emotional instability, who suffer from other
disabling co-morbid conditions that might contraindicate physical exercise (e.g. heart failure, chronic obstructive pulmonary disease orthopaedic conditions or
neurological disorders) are ineligible. All persons are
assessed by a cancer specialist (oncologist or surgeon)
regarding contraindications for high intensity exercise.
Persons without contraindications receive a brief information sheet about the Phys-Can study, and are

informed that there are no medical contraindications
for them to participate. Next, eligible persons are
contacted by one of the research staff and provided
with more detailed information, both written and verbal, and are given the opportunity to ask questions.
Those who agree to participate in the trial provide
written informed consent.
The Phys-Can study was approved by the Regional
Ethical Review Board in Uppsala, Sweden (Dnr 2014/249)
and registered in ClinicalTrials.gov (TRN = NCT02473003,
Oct, 2014).


Berntsen et al. BMC Cancer (2017) 17:218

Design

The design is a 2×2 factorial design where participants are
randomized to one of the following four groups (Fig. 1):
1) individually tailored high intensity exercise with
(H + BCTs) or
2) without BCTs (H)
3) individually tailored low-to-moderate intensity
exercise with (LM + BCTs) or
4) without BCTs (LM).
The RCT is stratified and within each stratum
randomization is carried out following a permuted
block design with 8 participants per block. The defined
strata are the three hospitals (Linköping, Lund and
Uppsala) and three cancer sites yielding 9 strata. When
all baseline measurements are finalized and reported in the

project’s electronic case report form, the randomization is
generated automatically in a web-portal (described below)
of participants to an exercise group according to predefined
strata (see above). The personnel in charge of recruitment
then contact the participant with information on study condition and the first visit to the gym is scheduled.

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All participants will exercise at least twice weekly for a
period of 6 months under the guidance of trained coaches. Training intensity is 40–50% (LM) or 80–90% (H)
of each individual’s heart rate reserve (Heart rate
reserve = HRpeak-HRrest) and maximal muscle
strength.

Sample size

The calculated sample size was based on detecting the
main factorial effects of each factor on Multidimensional
Fatigue Inventory (MFI) Physical Fatigue (PF) after completed intervention [32–34]. The target main effect size
was determined to be 2, which according to Purcell et al.
[35] is the minimal clinically important difference for
the MFI-PF. We assumed that the standard deviation
(SD) of PF was 5 in all four treatment arms, which is the
SD reported in Purcell et al. [35], Hagelin et al. [36] and
in an ongoing study within our research group (manuscript in preparation). Because three tests (two main and
one interaction effect) were planned, the 5% significance
level was adjusted using Bonferroni correction. In order
to have 80% power to detect a main factorial effect of 2

Fig. 1 Diagram of the participant flow through enrolment, baseline measurement, randomization, and follow-up. H = high intensity training;

L = low intensity training; BCT = Behaviour Change Technique


Berntsen et al. BMC Cancer (2017) 17:218

under the null hypothesis of no effect, 67 individuals in
each of the four treatment arms are needed, with a total
sample size of 268 individuals.
Further adjustments of the sample size were necessary
for several reasons. First, the sample size calculation was
based on the assumption of no interaction effects. However, Montgomery et al. [29] argue that, if anticipating
quantitative interactions, the trial should be powered to
detect those effects. Interaction effects often are much
smaller in size compared to the main effects. In clinical
trials, it is therefore rare to have 80% power to detect
the interaction effect. For instance, given the calculated
sample size in the present study, the trial would have a
power of only 22% to detect an interaction effect of 1.
However, in the present study a possible interaction between the factors is of clinical interest. Thus, the original
sample size was doubled, increasing the power to detect
the interaction between to approximately 50%. Second,
to account for missing data and drop-outs, the original
sample size was increased further by 30%. Third, given
that we include a baseline assessment, and assuming a
moderate correlation (0.3) between the MFI-PF at baseline and follow-up assessments, the sample size can be
reduced by approximately 10% [37]. Combining the
above, we concluded that including approximately 150
individuals in each treatment arm, 600 individuals in
total, should meet the statistical requirements of the
trial.

Description of interventions

All participants are offered guided exercise for 6 months.
This is equal to the most extensive adjuvant treatment
period with the exception for endocrine therapy which
may continue up to 10 years (for persons with breast
cancer). It is also an appropriate period of time to
achieve physical exercise effects and to establish a physically active lifestyle [22, 38]. Trained coaches will guide
both resistance and endurance exercise.
Resistance training

The resistance training will be performed at public gyms
during two supervised sessions per week. During the
first six weeks after inclusion the participants become familiar with the exercises and tests as well as how to use
the Omni-scale for self-reported perceived exertion [39]
included in the resistance program. During these six
weeks, there will be a progression in sets and power output as well as a reduction in the number of repetitions,
resulting in each participant having an individualized
program. The following exercises are included in the
program and performed on machines; seated leg press,
chest press, leg extension, seated row, seated leg curl,
and seated overhead press using dumbbells. In addition,
participants are instructed to do the following core

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exercises on a regular basis: sit-ups, the plank, bird-dog
and pelvic floor exercises.
The low-to-moderate intensity group exercises at 50%
of six- (the first weekly session) and ten repetitions maximum (the second weekly session) corresponding to 12

and 20 repetitions in three sets (reporting 5–7 on the
Omni-scale for perceived exertion (39)). Rest periods between sets are two and one minute for the two sessions,
respectively. The high intensity group exercises at six(the first weekly session) and ten repetitions maximum
(the second weekly session) corresponding to six and 10
repetitions in three sets (reporting 9–10 on the Omniscale for perceived exertion (39), with the last set continuing to failure. Rest periods between sets are two and
one minute for the two sessions, respectively. Relative
exercise intensity is adjusted over the remaining intervention period according to repeated measures of sixand ten repetitions maximum.
Endurance exercise

The first six weeks after inclusion the participants
familiarize themselves with the use of the heart rate
monitor and perceived exertion using the Borg-scale
[40] for monitoring of exercise intensity and perceived
exertion. Four endurance sessions are conducted at the
gym and supervised by a coach. Thereafter, the endurance exercise is home-based and followed up by a coach.
All participants are instructed to warm-up for approximately 10 min at moderate intensity before each endurance session. The participants are instructed to wear the
heart rate monitor during every session and report perceived exertion in a diary. Exercise frequency is recommended to be 2–4 times a week. The low-to-moderate
intensity group do continuous-based exercise (running,
cycling, walking uphill or any other endurance-based activity) in bouts of at least 10 min at an exercise intensity
of 40–50% of the heart rate reserve. The main aim is to
reach 150 min of moderate intensity per week. The high
intensity group conduct high-intensity interval exercise
at an exercise intensity of 80–90% of the heart rate reserve (at the end of the 3rd session) with two minutes
exercise (running, cycling, walking uphill or any other
endurance-based activity) and two minutes rest between
sessions. The participants start with five sessions, increasing to six after the six weeks familiarization period,
thereafter adding one session every fourth week until 10
sessions are reached as the maximum, corresponding to
75 min of vigorous intensity per week.
Behaviour change techniques

Self-regulatory BCTs are provided for the H + BCTs and
the LM + BCTs groups. These are strategies to facilitate
adherence to the high and low-to-moderate intensity exercise programs, respectively. These support strategies


Berntsen et al. BMC Cancer (2017) 17:218

focus on the adherence to the exercise intervention, primarily on the endurance exercise, as it is home-based,
and on maintaining exercise according to individual
preferences after the completion of the interventions.
The BCTs include a) behavioural goal-setting, b) shortterm action planning, c) self-monitoring, d) review of
behaviour goals, e) problem solving and functional behaviour analysis to identify affect individual-specific
determinants of exercise behaviour, and f ) long-term
coping planning to maintain physical exercise by own
choice after the intervention is completed. In addition,
motivational aspects are explored by initial interviews
based on a) previous experiences with physical exercise,
b) persons’ outcome expectations for following the exercise intervention as prescribed, c) persons’ anticipated
barriers and facilitators following the exercise intervention, and d) self-efficacy to partake in planned weekly
exercise. The BCTs are provided according to protocol,
but are individually tailored according to each participant’s need and functional behavioural analyses. Each
participant meets their coach on a regular basis during
the program, with gradually decreasing frequency in
order to enhance self-regulation at the end of the intervention. These coaching sessions take place either in
connection with the scheduled exercise sessions or via
phone. Participants with access to internet can use electronic and easily accessible self-monitoring of exercise
behaviour in a web portal developed for the Phys-Can
study (described below).
Education of coaches

Coaches (physiotherapists and personal trainers) have
been trained to provide the interventions in the four
groups. The education consisted of three common
course days for all coaches and three additional days for
those providing the BCT conditions with home assignments between course days. The education included lectures and seminars on cancer and cancer treatment,
exercise physiology, and repeated practice sessions in
the gym according to the intervention protocol on high
and low/moderate exercise. Additional lectures and
practice on exploration of motivation and use of BCTs
were given to coaches providing the BCT conditions.
Written intervention protocols have been developed,
specifying all intervention components in the four
groups. The coaches are to follow the protocol closely,
keep logs of attendance at gym sessions, check heart rate
during endurance sessions and monitor any adverse advents related to exercise. Adverse events caused by the
exercise are registered in a web-portal (described below).
Grade 1 (e.g. muscle strain) means that the participant
have to terminate the ongoing specific exercise but can
continue with the exercise session. Grade 2 (e.g. fall in
blood pressure) means that the participant must

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terminate the exercise session. Any severe adverse events
(e.g. fracture) are reported directly to the PI and managed by healthcare.
To address the coaches’ fidelity to the intervention
protocol, research staff visit the gyms repeatedly during
the intervention, giving feedback on both physical exercise and use of BCTs. Regular project group meetings
are held with all project personnel, where issues about

delivering the intervention are discussed and solved. In
addition, one coach representative from each study site
takes part in monthly Skype meetings where common issues relating to the intervention are discussed and coordinated. Coaches’ use of BCTs is monitored by audio
recordings of conversations between coaches and participants, and individual feedback is given by one of the
research staff.
Data monitoring and communication with persons

A web-portal has been designed. The aim of the PhysCan web portal is to facilitate collection of outcome
measures in the multiple study sites and to enable easily
accessible electronic self-monitoring of exercise behaviour. The participants sign on to the web portal and
complete forms related to outcome assessments and
self-monitoring of endurance training included as part
of the intervention (those who have no access to internet
fill out paper forms). The data base is located at Uppsala
University and constructed according to security principles from the Division of Security at Uppsala University.
All communication with the data base is encrypted and
backups are performed on a regular basis in order to secure data. The web portal automatically sends e-mails or
text messages to participants when the scheduled assessment is available, informing them to long on to the portal to complete the questionnaires. Participants also
receive reminders by e-mail or text messages. Those
who choose to complete paper forms receive the questionnaires and reminders by regular mail. The web portal also notifies research assistants by e-mail when an
assessment point is about to open for a specific participant and alerts the research assistants if questionnaires
are not completed within a set time frame. This enables
precise monitoring of time points for both participants
who use the web portal or choose to fill out paper forms.
At assessment points when blood samples, fitness tests
and recordings of physical activity are included, a research assistant contacts participants by phone to schedule an appointment.
Enrolment and outcomes (Fig. 2)
Primary outcome measures

Two Patient reported outcome measures (PROMs) are

used to assess CRF: The MFI [41] and the Functional
Assessment of Cancer Therapy: Fatigue, FACT-F [42].


Berntsen et al. BMC Cancer (2017) 17:218

Fig. 2 (See legend on next page.)

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Berntsen et al. BMC Cancer (2017) 17:218

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(See figure on previous page.)
Fig. 2 Enrolment and outcome measurements in Phys-Can intervention trial.
a
Midway through exercise intervention (3 months), b Directly after end of primary Oncological Treatment (OT), only participants receiving radiation
therapy or chemotherapy, c Directly after end of Exercise Intervention (EI), d After end of EI, e Self-reported data on physical activity, sleep onset/
end, and health economics are collected via diary during one week concurrently as wearing the Sensewear Armband. At T1, only sleep
onset/end and health economics are recorded, f In participants receiving chemotherapy or radiation therapy, these variables are collected at a
regular basis in clinical praxis. *MFI subscale physical fatigue

The MFI is a 20-item PROM and covers the following
dimensions: General Fatigue, Physical Fatigue, Mental
Fatigue, Reduced Motivation and Reduced Activity.

Secondary outcome measures

The EORTC QLQ-30 [43] and diagnosis-specific modules (QLQ-PR25 for prostate cancer, QLQ-BR25 for
breast cancer, QLQ-CR29 for colorectal cancer) are used
to assess HRQoL.
Mood is assessed with Hospital Anxiety and Depressions scale HADS [44] and Functioning in daily life with
the World Health Organization Disability Assessment
Schedule WHODAS II [45].
Readiness to change physical activity behaviour (The
Exercise Stage Assessment Instrument (ESAI) [46]), Exercise Barrier Self-Efficacy Scale (ESES) [47, 48], and
study specific questions about outcome expectation, progressive goal attainment and perceived behavioural control are used to assess cognitive-behavioural moderators
and mediators.
Cardiorespiratory fitness is measured as maximal
oxygen uptake during maximal walking/running until
exhaustion on a treadmill using a modified Balkeprotocol [49] starting at 4 km/h with an inclination
of 2%. The inclination increases with 1% each minute
until reaching 12%, from which the speed increases
0.5 km/h per minute until exhaustion. Self-perceived
exertion is recorded using a standardized Borg-scale
[40]. Oxygen consumption and minute ventilation are
measured continuously using an oxygen analyzer.
Heart rate is measured using a heart rate monitor.
Maximal upper and lower extremity muscle strength
is assessed as one repetition maximum including
chest press and seated leg press. Objectively monitored physical activity level, sedentary time and sleep
are recorded with SenseWear Armband Mini (BodyMedia
Inc., Pittsburgh, PA, USA), also found feasible and valid in
cancer persons [50, 51]. The participants wear the monitor for seven consecutive days. The cut off points defining
sedentary time and moderate-to-vigorous intensity physical activity are below 1.5 and above 3 metabolic equivalents (METs), respectively. The data from the monitor will
be downloaded and analysed with software developed by
the manufacturer (Sensewear Professional Research Software Version 8.1, BodyMedia Inc., Pittsburgh, PA, USA).

Medical and clinical background data are collected
from the records of the Regional Quality Registers and
from case records covering treatment administrated,
dose intensity, toxicity and adverse events according to
NCI-CTC 4.0 and time to cancer recurrence and survival. The Statistics and Result database (STORE) will be
used to obtain data on sick days and return to work.
The STORE database is managed by the Swedish Social
Insurance Agency, and contains information on social
insurance for all Swedish residents.
Data from several registries are included and data on
persons’ and relatives’ costs (time and money) related to
health care utilization will be collected. Euroqol EQ5D
[52] is used to calculate Quality-adjusted life years
(QALYs).
Blood samples are drawn and analysed for the levels of
IL-6, IL-8, IL-1β, TNF-α, P-CK-MB, P-CRP, IGF-1, BHbA1C, P- Cholesterol, P-HDL and P-LDL. Frozen sera
are saved in bio-banks for further analyses that can be
included later. Muscle cellular outcomes will be evaluated on muscle biopsies obtained form m. vastus lateralis in a subsample of women with breast cancer. A total
of 200 mg tissue will be collected at three time points;
before the start of adjuvant chemotherapy, in the middle
of treatment, and after the end of treatment. Muscle tissue will be divided into four pieces before further handling and freezing: 1) 20–30 mg in a nice bundle of fibres
is secured for later immunohistochemically analyses
(fibre area, fibre type, myonuclear number and satellite
cells), 2) 50 mg designated for later homogenization and
protein analyses (markers of cellular stress (HSPs and inflammatory markers), mitochondrial proteins, regulators
of cell size and structural proteins), 3) 30 mg is put in
RNA later for later RNA extraction and mRNA analyses,
4) 30 mg is put in RNA later for later morphological
analyses on single fibres (nuclear arrangements etc.).
Blood and biopsies are stored according to Swedish law

in bio-banks (Uppsala IVO ref. nr. 827, Linköping IVO
519, Lund IVO 136).
Statistical analysis

The data will be analysed according to the intention-totreat (ITT) principle, i.e. all participants will be analyzed
as randomized, regardless of whether they complete the
intervention as planned. The primary parameters of interests are the three factorial effects (2 main and one


Berntsen et al. BMC Cancer (2017) 17:218

interaction) after completed intervention. Each factorial
effect will be estimated taking into account the stratified
design following Imbens and Rubin [53]. Thus, we will
provide estimates for the overall factorial effects, which
are the primary parameters of interest, and also stratumspecific factorial effects which could facilitate external
validity. Baseline measurements will be included in the
analysis model to increase the precision of the estimates.
Drop-outs and missing values will be handled according to the following procedure. The main analysis will be
based on data where missingness is handled using multiple imputations by chained equations. The specification
of the multiple imputation model (e.g. choice of auxiliary
variables) will be decided after comparing the subject
characteristics in those with complete and incomplete
data. Under the assumption of missing at random
(MAR), an analysis based on multiple imputation conforms with the ITT. Due to the assumption of MAR,
which could be a strong assumption to make, factorial
effects will also be estimated using complete blocks only.
This is a result from the permuted block design which allows for unbiased estimation of the factorial effects using
the complete blocks only. Sensitivity analysis will conducted by comparing estimates from the two analyses
above with estimates based on complete cases only, a

pattern-mixture model, and tipping points analyses [54].

Discussion
The Phys-Can study aims to determine the effects of
low-to-moderate and high intensity physical exercise
with or without BCTs on CRF and HRQoL in persons
with cancer, both during treatment and in the longterm, post-treatment survivorship period. Additionally,
we will investigate the role of inflammation, cytokines
and gene expression in the development and maintenance of CRF, as well as the cost-effectiveness of physical
exercise programs during cancer treatment.
Systematic reviews underline the potential for physical
and psychosocial benefits from rehabilitation programs
including physical training [7]. Courneya et al. [10]
pointed out in a recent publication the top 10 research
questions related to physical training and cancer survivorship and several of them are covered in the present
study, e.g. to further investigate the optimal exercise prescription (e.g. intensity), if exercise reduces the risk for
cancer recurrence and influences treatment completion
rates, the role of behaviour change techniques and variables that may modify/mediate the responses to exercise.
The primary outcome of the present study is CRF
since that is one of the most common side effects in persons treated for cancer [7]. Based on data supporting the
beneficial effects of physical exercise during oncological
treatment, we will perform a large scaled, well-designed
study addressing the optimal level and intensity of

Page 9 of 12

exercise training to prevent or reduce fatigue and improve HRQoL of persons with cancer and cancer survivors. To also identify potential biological mechanisms
and underlying beneficial effects of exercise, blood samples will be analysed, and muscle biopsies obtained from
a sub-sample combining an experimental pre-clinical
part with an intervention implemented in the oncology

clinic.
We will also perform rigorous and maximal testing of
physical fitness to tailor the exercise program to the individual participant fitness level as recommended [22].
Carefully monitoring of perceived exertion, heart rate
monitors and number of repetitions and loads lifted is
important to control and adjust exercise intensity [26].
Furthermore, including BCTs to improve exercise adherence and maintain behavioural changes in the long-term
is highlighted as important [26].
The international research group includes experts
within oncology, exercise physiology, cell biology,
physiotherapy, psychology, cancer rehabilitation, health
economy and behavioural medicine, enabling a progressive approach to gain new knowledge. The project will
contribute with knowledge also to be used in clinical
practice by evaluating high versus low-to-moderate intensity physical exercise, as well as the use of BCTs to
adopt and maintain physical activity behaviour. Evaluating the effects of physical exercise as well as identifying
moderating and mediating variables on our outcomes
CRF and HRQoL can be expected to be beneficial on at
least three levels. Individual gains may be improved
well-being and quality of life, facilitated return to work,
and possibly reduced risk of cancer recurring. This in
turn may result in lower burden on the health care system, reduced societal costs positively influencing public
health. Implementation of the results into clinical practice will be facilitated by the close collaboration between
researchers and clinicians, and the fact that the study
intervention is performed in non-clinical settings. The
cooperation with public gyms outside healthcare is likely
to enable a smooth transition from study setting to
maintained exercise by self-management. During the
whole process, from planning to implementation of the
study, patient representatives are actively involved.
Methodological discussion

Even though the main aim of the present comparative
effectiveness study is to compare different exercise intensities on CRF and HRQoL, the lack of a randomized
usual care control group may be a limitation. Due to
strong evidence that physical exercise is beneficial for
persons during cancer treatment we considered it unethical to randomise persons to an untreated control group
that will not be offered exercise. To form a historical cohort, an observational study, was initiated and data


Berntsen et al. BMC Cancer (2017) 17:218

collected preceded the randomised study. Persons with
the same diagnosis and with the same inclusion/exclusion criteria as in the intervention study were included
in the cohort study at all three recruiting centres. The
inclusion started in September 2014 and ended immediately prior to start of inclusion to the intervention study.
A total of 95 participants were included in the observational study and will be followed for 10 years with same
outcomes measures as in the intervention study.
The sample size has been calculated to be 600 persons
in total, which is a challenge in a multicentre, complex
intervention study. However, a feasibility study (manuscript submitted) preceding the randomized study evaluated the inclusion procedures, settings, intervention
components, instruments, and tests.
The lesson learned from the feasibility study has contributed in several ways both to the final planning of the
Phys-Can trial. All the physical fitness tests, physical activity monitoring, and conducting exercise of low-tomoderate or high intensity, seem feasible to implement
in exercise oncology interventions. In addition, exercise
including resistance training with arm movements above
the head and repetitive muscle contractions of the arm
is feasible and may be safe for patients wearing a peripherally inserted central venous catheter (PICC) (a venous
access used for chemotherapy administration is a) due to
adjuvant chemotherapy. The results highlighted the need
for an enhanced learning and reporting regarding endurance exercise and checking of intensity levels. The results also implied that BCT do not have to target the

exercise behavior during supervised sessions; rather, the
support should target behaviors pertaining to unsupervised or home-based exercise.
In summary, the Phys-can study will contribute to our
understanding of the value of exercise and exercise intensity in preventing CRF and maintaining HRQOL during
and after treatment and, potentially, clinical outcomes as
well. It will also provide insights into possible biological
mechanisms through which exercise affects treatment outcomes. The value of BCTs in terms of adherence to, and
maintenances in, exercise behaviour in persons with cancer
will be evaluated. Implementation of the results into clinical
practice will be facilitated by the close collaboration between researchers and clinicians as well as the facts that the
study is performed in non-clinical settings (public gyms)
which may create a pathway between hospitals to society.

Page 10 of 12

reported outcome measures; QALYs: Quality adjusted life years;
WHODAS: World health organization disability assessment schedule
Acknowledgements
We would like to thank Arja Leppänen, Peter Nylund and Håkan Engman
who are patient representatives in the project.
Funding
This trial is funded by the Swedish Cancer Society (CAN 2012/621, CAN
2012/631, CAN 2015/414, The Swedish Research Council (K2014-99X), Nordic
Cancer Union and the World Cancer Research Fund (WCRF UK) and Wereld
Kanker Onderzoek Fonds (WKOF), as part of the World Cancer Research Fund
International grant program (2016/1635).
Availability of data and material
The datasets used and/or analysed during the current study available from
the corresponding author on reasonable request.
Authors’ contributions

SB, NA, LB, SB, ID, MH, PH, HI, BJ, RP, TR, GV, PÅ and KN contributed to the
design and writing of the study protocol. KN is the principal investigator of
this trial. All authors approved the final version of the manuscript.
Competing interests
The authors declare that they have no competing interests.
Consent for publication
Not applicable.
Ethics approval and consent to participate
This study (NCT02473003) has received ethical approval from the Regional
Ethical Review Board in Uppsala, Sweden (Dnr 2014/249) as a multi-centre
study. The participating hospitals are the university hospitals in Uppsala,
Linköping and Malmö/Lund. An informed consent is obtained from all
participants upon participation.

Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Author details
1
Dept. of Public Health and Caring Sciences, Lifestyle and rehabilitation in
long term illness, Uppsala University, Box 564, 75122 Uppsala, Sweden. 2Dept.
of Public Health, Sport and Nutrition, University of Agder, Gimlemoen 25,
4604 Kristiansand, Norway. 3Division of Psychosocial Research &
Epidemiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX,
Amsterdam, The Netherlands. 4Departments of Epidemiology & Biostatistics
and Medical Oncology, VU University Medical Center, PO Box 70577007 MB
Amsterdam, the Netherlands. 5Dept. of Medical and Health Sciences, Division
of Nursing Science, Linköping University Campus Valla, 581 83 Linköping,
Sweden. 6Division of Oncology and Pathology, Dept. of Clinical Sciences,
Lund University, Box 117, 221 00 Lund, Sweden. 7Centre of Inflammation and

Metabolism, Copenhagen University Hospital, Blegdamsvej 9, 2100
Copenhagen, Denmark. 8Experimental and Clinical Oncology, Dept. of
Immunology, Genetics and Pathology, Uppsala University, Box 564, 75122
Uppsala, Sweden. 9Dept. of Physical Performance, Norwegian School of Sport
Science, Sognsveien 220, 0863 Oslo, Norway. 10Leeds Institute of Cancer and
Pathology, St James’s University Hospital LEEDS LS9 7TF University of Leeds,
Leeds, UK. 11Dept. of Neuro Science, Physiotherapy, Uppsala University, Box
564, 75122 Uppsala, Sweden.
Received: 1 January 2017 Accepted: 14 March 2017

Abbreviations
BCT: Behaviour change techniques; CRF: Cancer related fatigue; EORTC QLQ30: The European organization for research and treatment of cancer quality
of life questionnaire; FACT-F: Functional assessments of cancer therapy;
HADs: Hospital anxiety and depression scale; HRQoL: Health related quality of
life; ITT: Intension to treat; MAR: Missing at random; MCID: Minimal clinically
important difference; METs: Metabolic equivalents; MFI: Multidimensional
fatigue inventory; MFI-PF: Multidimensional fatigue inventory-physical function; PICC: Peripherally inserted central venous catheter; PROMs: Patient

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